While follow-up of the 121,700 women in the Nurses' Health Study (NHS) will be supported by a pending UM1 (priority score=10), this competing renewal of PO1 CA87969, Dietary and Hormonal Determinants of Cancer in Women continues the scientific pursuit of modifiable determinants of breast, colorectal, and ovarian cancers. A primary, cross-cutting theme is the role of metabolites and metabolomic signatures in the etiology and progression of these cancers, including developing novel statistical approaches. Further, gene expression analyses of tumor tissue will enable us to identify pathways linking risk factors to cancer. The repeated measures of behavioral factors (eg, diet) since 1976, with our extensive biorepository (blood, urine, tumor tissue), allows us to thoroughly examine relations between behavior, biomarkers, and tumor expression. Although NHS has limited racial minorities, we include research to compare prevalence of metabolomic signatures predicting breast cancer in healthy white vs black participants as a step to understand racial differences in incidence, and an Aim to collaborate with the VITAL trial to identify colorectal adenoma to test if vitamin D supplements may be particularly beneficial in blacks (building on previous research in this PO1 finding relations of vitamin D to adenoma). Briefly, Project 1 will test whether: specific metabolites and metabolomic signatures are associated with breast cancer risk and survival; metabolomics or gene expression patterns are etiologic factors underlying the relation of diet to breast cancer; energy balance and insulin resistance (eg, strength training, diet, metformin use) are associated with breast cancer risk and survival, including according to tumor expression. Project 2 will examine whether: metabolites/ metabolomic signatures are associated with colorectal cancer risk and survival; energy balance and insulin resistance are associated with colorectal cancer risk and survival, including according to tumor expression; how anti-inflammatory agents (eg, aspirin) reduce colorectal cancer, with extensive consideration of etiologic pathways; and supplemental vitamin D reduces colorectal adenoma in blacks and whites in a randomized trial. Project 3 will examine whether lipid metabolites and metabolomic signatures and inflammation-associated exposures are related to ovarian cancer, including according to tumor expression, and will initiate novel research into ovarian cancer survival. Project 4 will develop statistical approaches to analyzing metabolomics data, and to predicting cancer risk. In summary, these highly interrelated Projects will enhance our understanding of the etiology and progression of cancer and potential preventive strategies.